Loss of bone with advancing age is accompanied by oxidative stress (OS) and reduced bone formation associated with diminished osteoblast number and increased osteoblast apoptosis. However, the molecular mechanisms underlying these changes are poorly understood; and it is unclear how intermittent administration of parathyroid hormone (PTH) stimulates bone formation in the elderly in the face of these pathologic changes. It is hypothesized that lipid oxidation, the same mechanism implicated in the pathogenesis of atherosclerosis, also adversely affects bone metabolism. Specifically, the lipoxygenase Aloxl 5 causes OS in the skeleton by oxidizing polyunsaturated fatty acids to generate the pro-oxidant 4- hydroxynonenal (4-HNE), leading to activation of p66 [Shc] - a redo signaling protein that further amplifies OS. The combined effects of OS and lipid oxidation reduce the differentiation and survival of osteoblasts via PPARy-mediated actions that decrease Wnt signaling. It is also proposed that PTH attenuates OS by decreasing p66[Shc] activation, suppressing AloxIS expression, and increasing the synthesis of the 4-HNE scavenging enzyme aldehyde dehydrogenase 3a1 (Alclh3a1). To advance these interrelated hypotheses, the contribution of Aloxl5-mediated generation of 4-HNE to the OS and bone loss caused by aging, ovariectomy, or hyperiipidemia in the ApoE knockout (ApoE KO) mouse model of atherosclerosis, will be determined by conditional deletion of Aloxl 5 or conditional overexpression of Aldh3a1. The contribution of OS and PPARy activation to the decline in Wnt signaling, osteoblast number and bone mass in these models will be investigated by deletion of p66[hsc], and by conditional deletion of PPARy from osteoblast progenitors. Finally, the contribution of the anfioxidant property of intermittent PTH to its anabolic efficacy will be studied in aged mice or ApoE KO mice in which OS has been reduced by deletion of p66 [Shc]' We will also investigate the signaling pathways and anti-oxidant enzymes underlying the ability of PTH to attenuate OS. Efforts to determine the contribution of lipid oxidation to the loss of bone mass in aged and hyperlipidemic atherosclerotic mice could establish common mechanisms for osteoporosis and atherosclerosis, and eventually lead to new therapies that simultaneously combat osteoporosis and other age-related diseases. Elucidation of the relevance of PTH-mediated suppression of OS and lipid oxidation to its anabolic efficacy may reveal new approaches for the treatment of osteoporosis.